Apnea e reflusso gastroesofageo nel neonato pretermine

Objective: To document the existence of a relationship between apnea of prematurity (AOP) and gastroesophageal reflux (GER) in preterm infants. Setting: One Neonatal Intensive Care Unit Patients: Twenty-six preterm infants (gestational age<32 weeks) with recurrent apneas. Intervention: Simultaneous and synchronized recording of polysomnography and pH-impedance monitoring (pH-MII). Polysomnography detects and characterizes apneas, by recording of breathing movement, nasal airflow, electrocardiogram, pulse oximeter saturation. pH-MII is the state-of-theart methodology for GER detection in preterm newborns. Main outcome measures: Relationship between AOP and GER, which were considered temporally related if both started within 30 seconds of each other. Results: One-hundred-fifty-four apneas out of 1136 were temporally related to GER. The frequency of apnea during the one-minute time around the onset of GER was significantly higher than the one detected in the GER-free period (p=0.03). Furthermore, the frequency of apnea in the 30 seconds after GER (GER-triggered apneas) was greater than that detected in the 30 seconds before (p=0.01). A great inter-individual variability was documented in the proportion of GERtriggered apneas. A strong correlation between total number of apneas and the difference between apneas detected 30 seconds after and before GER was found (p=0.034). Conclusions: Our data show that a variable rate of apneas can be triggered by GER in very preterm infant. Further studies are needed to recognise clinical features which identify those patients who are more susceptible to GER-triggered apneas.

Development of Clinical Decision Support Systems based on Mathematical Models of Physiological Systems

In the last years of research, I focused my studies on different physiological problems. Together with my supervisors, I developed/improved different mathematical models in order to create valid tools useful for a better understanding of important clinical issues. The aim of all this work is to develop tools for learning and understanding cardiac and cerebrovascular physiology as well as pathology, generating research questions and developing clinical decision support systems useful for intensive care unit patients. I. ICP-model Designed for Medical Education We developed a comprehensive cerebral blood flow and intracranial pressure model to simulate and study the complex interactions in cerebrovascular dynamics caused by multiple simultaneous alterations, including normal and abnormal functional states of auto-regulation of the brain. Individual published equations (derived from prior animal and human studies) were implemented into a comprehensive simulation program. Included in the normal physiological modelling was: intracranial pressure, cerebral blood flow, blood pressure, and carbon dioxide (CO2) partial pressure. We also added external and pathological perturbations, such as head up position and intracranial haemorrhage. The model performed clinically realistically given inputs of published traumatized patients, and cases encountered by clinicians. The pulsatile nature of the output graphics was easy for clinicians to interpret. The manoeuvres simulated include changes of basic physiological inputs (e.g. blood pressure, central venous pressure, CO2 tension, head up position, and respiratory effects on vascular pressures) as well as pathological inputs (e.g. acute intracranial bleeding, and obstruction of cerebrospinal outflow). Based on the results, we believe the model would be useful to teach complex relationships of brain haemodynamics and study clinical research questions such as the optimal head-up position, the effects of intracranial haemorrhage on cerebral haemodynamics, as well as the best CO2 concentration to reach the optimal compromise between intracranial pressure and perfusion. We believe this model would be useful for both beginners and advanced learners. It could be used by practicing clinicians to model individual patients (entering the effects of needed clinical manipulations, and then running the model to test for optimal combinations of therapeutic manoeuvres). II. A Heterogeneous Cerebrovascular Mathematical Model Cerebrovascular pathologies are extremely complex, due to the multitude of factors acting simultaneously on cerebral haemodynamics. In this work, the mathematical model of cerebral haemodynamics and intracranial pressure dynamics, described in the point I, is extended to account for heterogeneity in cerebral blood flow. The model includes the Circle of Willis, six regional districts independently regulated by autoregulation and CO2 reactivity, distal cortical anastomoses, venous circulation, the cerebrospinal fluid circulation, and the intracranial pressure-volume relationship. Results agree with data in the literature and highlight the existence of a monotonic relationship between transient hyperemic response and the autoregulation gain. During unilateral internal carotid artery stenosis, local blood flow regulation is progressively lost in the ipsilateral territory with the presence of a steal phenomenon, while the anterior communicating artery plays the major role to redistribute the available blood flow. Conversely, distal collateral circulation plays a major role during unilateral occlusion of the middle cerebral artery. In conclusion, the model is able to reproduce several different pathological conditions characterized by heterogeneity in cerebrovascular haemodynamics and can not only explain generalized results in terms of physiological mechanisms involved, but also, by individualizing parameters, may represent a valuable tool to help with difficult clinical decisions. III. Effect of Cushing Response on Systemic Arterial Pressure. During cerebral hypoxic conditions, the sympathetic system causes an increase in arterial pressure (Cushing response), creating a link between the cerebral and the systemic circulation. This work investigates the complex relationships among cerebrovascular dynamics, intracranial pressure, Cushing response, and short-term systemic regulation, during plateau waves, by means of an original mathematical model. The model incorporates the pulsating heart, the pulmonary circulation and the systemic circulation, with an accurate description of the cerebral circulation and the intracranial pressure dynamics (same model as in the first paragraph). Various regulatory mechanisms are included: cerebral autoregulation, local blood flow control by oxygen (O2) and/or CO2 changes, sympathetic and vagal regulation of cardiovascular parameters by several reflex mechanisms (chemoreceptors, lung-stretch receptors, baroreceptors). The Cushing response has been described assuming a dramatic increase in sympathetic activity to vessels during a fall in brain O2 delivery. With this assumption, the model is able to simulate the cardiovascular effects experimentally observed when intracranial pressure is artificially elevated and maintained at constant level (arterial pressure increase and bradicardia). According to the model, these effects arise from the interaction between the Cushing response and the baroreflex response (secondary to arterial pressure increase). Then, patients with severe head injury have been simulated by reducing intracranial compliance and cerebrospinal fluid reabsorption. With these changes, oscillations with plateau waves developed. In these conditions, model results indicate that the Cushing response may have both positive effects, reducing the duration of the plateau phase via an increase in cerebral perfusion pressure, and negative effects, increasing the intracranial pressure plateau level, with a risk of greater compression of the cerebral vessels. This model may be of value to assist clinicians in finding the balance between clinical benefits of the Cushing response and its shortcomings. IV. Comprehensive Cardiopulmonary Simulation Model for the Analysis of Hypercapnic Respiratory Failure We developed a new comprehensive cardiopulmonary model that takes into account the mutual interactions between the cardiovascular and the respiratory systems along with their short-term regulatory mechanisms. The model includes the heart, systemic and pulmonary circulations, lung mechanics, gas exchange and transport equations, and cardio-ventilatory control. Results show good agreement with published patient data in case of normoxic and hyperoxic hypercapnia simulations. In particular, simulations predict a moderate increase in mean systemic arterial pressure and heart rate, with almost no change in cardiac output, paralleled by a relevant increase in minute ventilation, tidal volume and respiratory rate. The model can represent a valid tool for clinical practice and medical research, providing an alternative way to experience-based clinical decisions. In conclusion, models are not only capable of summarizing current knowledge, but also identifying missing knowledge. In the former case they can serve as training aids for teaching the operation of complex systems, especially if the model can be used to demonstrate the outcome of experiments. In the latter case they generate experiments to be performed to gather the missing data.

Exploratory analysis of the role of circulating microRNA in metastatic melanoma patients

MicroRNAs act as oncogene or tumor suppressor gene regulators and are actively released from tumor cells in the circulation. Specific microRNAs can be isolated and quantified in the blood, usually in serum or plasma fractions, where they are uncommonly stable. Cell-free microRNAs serve many, and possibly yet unexplored, functional roles and microRNA levels reflect underlying conditions and have been associated with skin cancer presence, stage and evolution. However, the clinical potential of circulating miRNAs in metastatic melanoma remains largely undefined. From May 2020 to September 2022, we conducted a spontaneous, monocentric, exploratory study on human tissues in vitro, which aimed to evaluate the prognostic and predictive role of circulating miRNAs in metastatic melanoma patients. At the Medical Oncology Unit of Policlinico Sant’Orsola-Malpighi of Bologna, peripheral venous blood samples from patients with metastatic melanoma treated with checkpoint inhibitors (CPI) were collected before the start of CPI (baseline, T0) and longitudinally, approximately every 3 months (T1, T2, etc). Circulating miRNA quantification was performed by droplet digital PCR (Biorad) using an EvaGreen and LNA primer-based assays. QuantaSoft Program (Biorad) calculated the absolute quantifications of each miRNA, indicated as copies/µL. After analysis of the literature, we chose to analyze miR-155-5p, miR-320a and miR-424-5p level. All miRNAs except miR-424-5p show a significantly higher level in plasma of patients who are alive after 1 year of follow-up. High/low levels of baseline miR-155-5p, miR-320a and miR-424-5p are significantly associated with overall survival and progression-free survival. Furthermore, a preliminary analysis on the group of patients who received first-line with anti-PD-1 (N=7), baseline miR-155-5p shows higher levels in responder vs. non responder patients (p 0.06). These data, though promising, are preliminary and need to be further investigated in a larger cohort of patients.